1. Field of the Invention
The present invention relates to novel benzopyranyl guanidine derivatives of formula 1. IL also relates to process for preparing the novel compounds and pharmaceutical formulations comprising one or more of the compounds as an active ingredient.
The present invention also relates to pharmaceutical use of the benzopyranyl guanidine derivatives. In particular, the present invention is pharmacologically useful in the protection of heart, neurconsonal cell or brain injury, or preserving organs, and also pharmacologically useful for inhibition of NO generation, lipid peroxidation, angiogenesis or restenosis. ##STR2##
Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n and * are each defined in specification.
2. Description of the Prior Art
Ischemic heart diseases usually occur as a result of myocardial ischemia, when the oxygen supply is significantly decreased compared to the oxygen demand due to the imbalance between them. In most cases, a coronary artery disorder was found to be a main reason of the ischemic heart diseases. If the inner diameter of coronary artery becomes narrow, the blood supply, resulting in oxygen supply, becomes insufficient, which can cause angina pectoris, myocardial infarction, acute cardioplegia, arrhythmia, and so on (G. J. Grover, Can. J. Physiol. 75, 309 (1997); G. D. Lopaschuk et al., Science & Medicine 42 (1997)). Because ischemic heart diseases are also caused by other complex factors besides coronary artery disorders, drug therapy as well as operational method such as perculaneous transluminal coronary angioplasty (PTCA) is required for its treatment. For that purpose, several drugs are being used, including anti-thrombotic agents, arteriosclerosis curatives, especially by beta blockers, nitrate, calcium antagonists such as nifedipin, thromobolytics, aspirin, and angiotensin converting enzyme (ACE) inhibitors.
Differently from conventional potassium channel openers, the pyranyl guanidine compound (BMS-180448) represented by the following formula 2, has been reported to act selectively on ATP-sensitive potassium channels (K.sub.ATP) located in the heart (K. S. Atwal et al. , J. Mde. Chem. 36, 3971 (1993); K. S. Atwal et al., J. Me. Chem. 38, 1966 (1995)). The BMS 180448 compound was found to protect ischemic hearts without a significant lowering of blood pressure, which gives the prospects for novel drug development as a cardionprotectant. ##STR3##
Both global and focal ischemia initiate progressive cellular changes, which lead to ischemic brain injury (M. D. Ginsburg, Neuros Scientist 1, 95 (1995)). Even after blood flow is restored, oxygen can enhance the biochemical reactions that generate free radicals, which can lead to a potential for "reperconsfusion injury" to occur. In order to prevent the brain injury caused by ischemia-reperfusion, the brain must be protected during ischemic period to avoid additional injury and pathological progressive cellular to changes have to be minimized. For that purpose, neuroproteconstives such as excitatory amino acid antagonists and anti-oxidants are being used.
Damage or death of neurons is known to be a main cause for various neurological disorders such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, infant asphyxia, glaucoma and daiabetic neuropathy, etc. (G. J. Zoppo et al., Drugs 54, 9(1997); I. Sziraki et al., Neurosci. 85, 110(1998)). Neurons are damaged by various consfactors and typically by increase in iron concentration, reactive oxygen species, and peroconsxidants within neurons (M. P. Mattson et al. , Methods Cell Biol. 46, 187 (1995); Y. Goodman et al., Brain Res. 706, 328 (1996)).
An increase of iron concentration in neuronal cells induces the formation of highly reactive hydroxyl radicals. An excess of oxygen free radicals facilitates lipid peroxidation, so that peroxidants are accumulated in neurons. The reactive free radicals accumulated in cells are known o be responsible for inflammatory diseases such as arthritis; atherosclerosis; cardiac infarction; and neurodegenerative disease such as dementia as well as acute and chronic injury of tissues and organs caused by ischemia-reperfusion or by endotoxins via bacterial infection.
Therefore, therapeutic approaches to minimize the damage or death of neurons have been pursued, including the inhibition of lipid peroxidation, NO formation, and reactive oxygen species induced by endotoxins. To date, anti-oxidants are reported to ameliorate the neuronal damage and death caused by an increase of iron concentration within neurons. Much effort has been continued to develop pharmaceutical drugs which are able to prevent neuronal damage by oxidative stress (Y. Zhang et al., J. Cereb. Blood Flow Metab. 13, 378 (1993)).
Infant asphyxia (IA), triggered by transient deficiency of oxygen supply during delivery, was reported to be caused by the reduction of energy production, damage of cell membrane due to oxygen free radical, release of excitatory neurotransmitters, change of intracellular ion concentrations including calcium, zinc, etc. IA is a major worldwide problem, because if IA is severe, the chances of mortality are high (around 1/3 of the cases) [C. F. Loid et. al. Physiology and Behavior 68; 263-269 (2000)]. In addition, it can produce long term sequela such as movement disorders, learning disabilities, epilepsy, dystonia, mental retardation, and spasticity.
Antioxidant enzymes, allopurinol, Vitamine C & E, free radical scavengers, inhibitors of excitatory neurotransmitters, calcium channel blockers such as nimodipinconsa and flunarizine, inhibitors of NO formation, hyperglycemic and hypothermic therapy may be beneficial for the protection of brain injury, but their clinical application is still limited. Thus more intensive research is required to treat infant asphyxia properly.
Glaucoma, one of the leading causes of blindness, is defined as an optic neuropathy associated with characteristic changes in optic nerve. In humans, the optic nerve consists of 1 million axons from neurons whose perikarya reside primarily in the ganglion cell layer and, to a less extent, in the inner part of the inner nuclear layer. The excavated appearance of the optic nerve head in glaucoma is thought to be caused by the death and subsequent loss of ganglion cells and their axons [N. N. Osborne, et. Al. Survey of Ophthalmology, 43; suppl. S102-s128 (1999)]. Neuroprotective agents in glaucoma may protect death of retinal neurons, in particular the ganglion cells, either directly or indirectly. A variety agents such as NMDA receptor antagonist, .beta.-blockers, calcium antagonists, and antioxidants can be used to protect the death of retinal neurons induced by ischemia.
Although the pathogenesis of diabetic neuropathy has not been clearly established, two main hypotheses have been proposed for it. One is metabolic abnormalities, and the other is blood flow deficits in peripheral nerve [K. Naka et. Al. Diabetes Research and Clinical Practice, 30: 153-162 (1995)]. Acetyl-L-carnitine (ALC) by stimulating metabolism of lipid and improving impaired nociceptive responses of neurons, and Prosaptide by releasing neutrophic factors are in clinical trials. In addition, memantime showing good effects on vascular dementia through the regulation of NMDA receptor, is pursuing clinical trial. Then, neuroprotective agents having a variety of mechanisms of action may be developed to treat diabetic neuropathy.
The ratio of cancer in human diseases is being gradually increased. Angiogenesis, formation of new blood vessels, is recognized as the core process for growth and metastasis of solid tumors (Folkma, J. et al., J. Biol. Chem. 267: 10931-10934 (1992)). Angiogenesis is controlled by inducers and inhibitors of angiogenesis. When the balance between them is broken, that is, when angiogenesis inducers prevail over angiogenesis inhibitors, a large quantity of new blood vessels are formed. Angiogenesis is closely related to various physiological phenomena, such as embryonic development, wound healing, chronic inflammation, hemangiomas, diabetic retinopathy, rheumatoid arthritis, psoriasis, AIDS complications, and the growth and metastasis of malignant tumors (Forkman, J., Klagsbrun. M. Science 235: 442-447 (1987)). Angiogenesis includes a series of processes such as the migration, proliferation and differentiation of endothelial cells, and is an important prerequisite for the growth and metastasis of cancers. Tn detail, because the growing tumor cells require the formation of blood vessels from host cells, angiogenesis promotors derived from tumors stimulate to induce the angiogenesis into the consumor mass. Afterwards, the blood vessels formed around the malignant tumors facilitate to metastasize the tumor cells to other sites. Therefore, the inhibition of angiogenesis leads to the prevention of the growth and metastasis of cancers. As one of the important research areas for the developing of anti-cancer drugs, extensive attention is paid to the finding of angiogenesis inducers and angiogenesis inhibitors and the revealing of their working mechanisms.
Thus far, proteins such as prostamine and tumor necrotic factors, factors derived from cartilage tissues, and cortisone called angiostatic steroids and various steroid derivatives, have been found to be able to play roles as angiogenesis inhibitors. In particular, hydrocortisone exhibits anti-angiogenetic activity by cotreatment with heparin (Lee, A. et al., Science 221: 1185-1187 (1983); Crum, R. et al., Science 230: 1375-1378 (1985)). However, these compounds have a potential problem to treat cancers effectively owing to their cytotoxicity.
Percutaneous coronary interventions (PCI) play an important role in the management of coronary artery stenosis, narrowing of the lumen as a result of growth of an atherosclerotic plaque in the intima (Inner coat) of the vessel, with success rate of more than 95%, but these are complicated by significant renarrowing of the artery (restenosis) in 20-50% of patients with 6 months after the intervention (Bult, H. Tips, 21; 274-279 (2000)). The biology of restenosis is not completely understood, but the predominant cellular mechanisms that contribute to restenosis include thrombosis, vascular smooth muscle cell migration and proliferation, and adventitious scarring. Different form atherosclerosis, restenosis is not dependent on the concentration or composition of atherogenic plasma lipids.
Finding effective therapies for restenosis has been difficult because of incomplete understanding of biology of restenosis and the lack of suitable animal models. Some drug classes, glycoprotein IIb/IIIa antagonist, antioxidant probucol, have recently demonstrated potential benefits in clinical trials (Bult, H. Tips, 21; 274-279 (2000)). Since angiogenesis restenosis is characterized by intensive proliferative activity, then development of drugs to reduce vascular smooth muscle cell proliferation are being pursued.
The intensive research on the development of compounds with the above-mentioned pharmacological efficacies by the inventors, found that the benzopyranyl guanidine derivatives represented by the formula 1 have superior cardioprotective and neuroprotective activity from ischemia-reperfusion and hypoxic damage. The compounds also exhibit various pharmacological efficacies, including protection of neurons, prevention of lipid peroxidation and reactive oxygen species formation, protection of ischemic retina, improvement of impaired nociceptive responses in diabetic rats, inhibition of NO formation, and suppression of angiogenesis and restenosis. Thus the compound of the present invention can be useful in the prevention and treatment of various diseases related to cardiovascular system such as cardiac infarction and congestive heart failure; stroke; neuronal damage such as infant asphyxia, glaucoma, diabetic neuropathy and head trauma; oxygen free radical-related disease such as neurodegenerative diseases and atherosclerosis; angiogenesis such as cancers and diabetic retinopathy, or restenosis, and also can be used in protecting preserving organs such as heart, kidney, liver, and tissues and protecting organs in major cardiovascular surgery.